Three medications are approved by the FDA as treatments for alcohol dependence: disulfiram, acamprosate and naltrexone, but these are seldom prescribed due to poor efficacy or side effects. Another, topiramate, is effective for reducing alcohol use but it causes a range of side effects that limit its tolerability. Another clas of potentially effective treatments includes triple uptake inhibitors. Triple uptake inhibitors enhance neural signaling that is mediated by serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Two triple uptake inhibitors (DOV 102,677 & amitifadine/DOV 21,947) have been shown to reduce alcohol self-administration in rodents. In a pilot study we showed that a newly developed triple reuptake inhibitor, SKL 10406, reduced alcohol intake in rodents as well. We now propose to evaluate SKL 10406 as a new treatment for alcohol dependence. Phase I Specific Aim: To conduct a human laboratory safety evaluation (n=20) of SKL 10406 (25, 50, and 75 mg PO BID) alone and combined with alcohol in alcohol-experienced healthy volunteers. Dose escalation and stopping rules are in place. This study will characterize the side effects, safety profile, and maximum tolerated dose of SKL 10406 when combined with an intoxicating dose of alcohol. Milestone: we will identify a dose of SKL 10406 that when combined with alcohol does not cause unacceptable toxicity, defined as more than one SAE at the lowest dose of SKL 10406. Phase II Specific Aim: To conduct a double-blind, randomized placebo-controlled outpatient clinical trial of SKL 10406 as a treatment for alcohol dependence (n=72). The primary outcome measure will be proportion of self-reported heavy drinking days (e5 drinks/day for males and e4 drinks/day for females) over the course of the study (imputing dropouts as baseline rate), a standard outcome in clinical trials for alcohol dependence.